Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies

Joan Montero; Cécile Gstalder; Daniel J. Kim; Dorota Sadowicz; Wayne Miles; Michael Manos; Justin R. Cidado; J. Paul Secrist; Adriana E. Tron; Keith Flaherty; F. Stephen Hodi; Charles H. Yoon; Anthony Letai; David E. Fisher; Rizwan Haq

doi:10.1038/s41467-019-12477-y

Nature Communications (Nov 2019)

Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies

Joan Montero,
Cécile Gstalder,
Daniel J. Kim,
Dorota Sadowicz,
Wayne Miles,
Michael Manos,
Justin R. Cidado,
J. Paul Secrist,
Adriana E. Tron,
Keith Flaherty,
F. Stephen Hodi,
Charles H. Yoon,
Anthony Letai,
David E. Fisher,
Rizwan Haq

Affiliations

Joan Montero: Division of Hematologic Neoplasia/Malignancies, Dana-Farber Cancer Institute, Harvard Medical School
Cécile Gstalder: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Daniel J. Kim: Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School
Dorota Sadowicz: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Wayne Miles: Department of Molecular Genetics, The Ohio State University
Michael Manos: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Justin R. Cidado: Bioscience, Oncology IMED Biotech Unit
J. Paul Secrist: Bioscience, Oncology IMED Biotech Unit
Adriana E. Tron: Bioscience, Oncology IMED Biotech Unit
Keith Flaherty: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School
F. Stephen Hodi: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Charles H. Yoon: Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School
Anthony Letai: Division of Hematologic Neoplasia/Malignancies, Dana-Farber Cancer Institute, Harvard Medical School
David E. Fisher: Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School
Rizwan Haq: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School

DOI: https://doi.org/10.1038/s41467-019-12477-y
Journal volume & issue: Vol. 10, no. 1
pp. 1 – 15

Abstract

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MAPK-targeted therapies fail to achieve complete remission. Here, the authors show that anti-apoptosis resistance is acquired in these targeted therapies through the mRNA destabilization of NOXA which leads to dependence on MCL-1, and that sequential combination of MCL-1 inhibition with targeted therapies overcomes this resistance.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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